Functional interference between estrogen-related receptor alpha and peroxisome proliferator-activated receptor alpha/9-cis-retinoic acid receptor alpha heterodimer complex in the nuclear receptor response element-1 of the medium chain acyl-coenzyme A dehydrogenase gene

Abstract

We undertook a study of molecular interference of nuclear orphan receptors. Nuclear receptor response element-1 (NRRE-1) from the human medium-chain acyl coenzyme A dehydrogenase (MCAD) gene promoter was shown to contain three hexamer elements (site 1 through 3) that are known to interact with a number of nuclear receptors including chicken ovalbumin upstream promoter transcription factor (COUP-TF) and estrogen-related receptor alpha (ERRα). We demonstrated that the peroxisome proliferator-activated receptor alpha/9-cis-retinoic acid receptor alpha (PPARα/RXRα) heterodimer complex can also bind to the two hexamer repeat sequences (between site 1 and site 3) arranged as an everted imperfect repeat separated by 14 bp (ER14). Mutations of the putative core elements have shown that these three sites are differentially involved in ERRα and PPARα/RXRα binding. Homodimer of ERRα was shown to interact between site 1 and site 3 (ER14). To date, no nuclear receptor is known to bind to response elements over such long intervals. Interestingly, site 1 was shown to be essential for ERRα binding while site 3 supports its binding only in the presence of site 1. Furthermore, it was shown that the binding profile of ERRα and PPARα/RXRα are competitive rather than making a high order complex within NRRE-1. At the cellular level, transcriptional activation driven by the PPARα/RXRα complex was counteracted by the expression of ERRα in HeLa cells. These results suggest that ERRα and PPARα/RXRα could interfere with each other's function through binding to similar DNA elements, thereby finetuning the transcriptional outcome of the target gene. Our findings suggest a mechanism whereby multiple nuclear receptors can activate or repress DNA binding or transcription via a single pleiotropic regulatory element.

DNA‐binding profiling of human hormone nuclear receptors via fluorescence correlation spectroscopy in a cell‐free system

“…Nuclear receptor response element (NRRE)-1 (À341/À307), a pleiotropic element present in the MCAD gene promoter [9], is known to interact with a number of NHRs including the RXR and estrogen related receptor (ERR). Maehara et al previously reported that the ERR, but not the PPAR, bound to the NRRE-1 as a homodimer or as two independent monomers [10]. Consistent with this report, we also found that the ERRc bound to the NRRE-1, whereas the PPARa (a negative control) did not ( Fig.…”

Interplay between estrogen-related receptor alpha (ERRα) and gamma (ERRγ) on the regulation of ERRα gene expression

“…It is unusual for a nuclear receptor to bind two ERE half site with such wide space in between. Nonetheless, ERRγ has been reported to bind a broad range of sequences, including the monovalent binding sites (Razzaque et al, 2004), whereas ERRα also binds variety of response sequences (Barry et al, 2006;Johnston et al, 1997) including the NRRE-1 of the medium chain acyl-coenzyme A dehydrogenase (MCAD) gene at sites with 14 bases in the middle (Maehara et al, 2003). Recently, Giguere's laboratory demonstrated that a single nucleotide change in ERRα binding site can affect the mode of PGC-1α activation of its target promoters (Barry et al, 2006).…”

Dietary clofibrate inhibits induction of hepatic antioxidant enzymes by chronic estradiol in female ACI rats

“…Although it is known that some peroxisome proliferators, such as butylbenzyl phthalate, a phthalate ester used as plasticizer, are capable of interacting with estrogen receptors (Zacharewski et al, 1998;Fujita et al, 2003), clofibrate is not known to interact directly with estrogen receptors (Ashby et al, 1997). A recent report suggests that gene transcription mediated via estrogen receptor alpha can be attenuated by PPAR␣/RXR␣ compexes that bind to similar DNA elements (Maehara et al, 2003). The ACI rat model provides a valuable model to gain further insights into potential ER-independent events.…”